PROJECT SUMMARY There is a critical lack of effective therapies for neuropsychiatric diseases because the neurochemistry underlying these illnesses is not well-understood. The prevalence of neuropsychiatric diseases is predicted to increase, placing augmented stress on individual sufferers and their caregivers and families. The collective loss of productivity here creates heavy economic burdens. Therefore better understanding the neurochemistry of mental disorders is a pertinent and fundamental task required to design effective treatments. The long-term goal of the proposed research is to establish how mechanisms that regulate extracellular serotonin and histamine in vivo alter during mental illness. The first steps towards this goal, as outlined in the objectives of the proposal are to are to enable precise, simultaneous in vivo chemical measurements of serotonin and histamine and to create models that mathematically describe how these two messengers are physiologically regulated in the extracellular space. The central hypothesis here is that serotonin and histamine rapidly modulate each other's chemistry. This central hypothesis stems from our preliminary data showing that histamine rapidly, inversely modulates serotonin in the premammillary nucleus via H3 receptors and that serotonin transporters reuptake histamine (a transporter for histamine has not yet been identified). The rationale is that understanding the physiological mechanisms that regulate extracellular in vivo serotonin and histamine will enable a systematic exploration of the roles of these two neurotransmitters in different neuropsychiatric pathophysiologies, opening and advancing novel treatment strategies. Guided by preliminary data, an interdisciplinary approach will test the central hypothesis via two specific aims: 1. Perform real-time, simultaneous measurements of serotonin and histamine in vivo and 2. Determine mechanisms underlying co- regulation of extracellular serotonin and histamine. In aim 1, a cutting edge electroanalytical technique will be developed to provide the first real-time simultaneous measurements of serotonin and histamine in vivo. In specific aim 2, a powerful interdisciplinary collaboration between chemists and mathematicians will unravel serotonin and histamine co-regulatory mechanisms in vivo. The approach is innovative because it brings advanced analytical techniques and mathematics together to tackle important analytical and neuroscience challenges. The proposed research is significant because it can set the stage for us to systematically study how serotonin and histamine alter during different neuropsychiatric diseases, enriching the chemical scope of information that drug developers have available to create more effective therapies. This will benefit individuals, society and the economy. The research will also have impact on a much broader research agenda. The analytical methodology that simultaneously measures serotonin and histamine in real-time and models that describe how these two messengers are regulated in vivo are extremely valuable to researchers wishing to study the plethora of disorders in which serotonin and histamine are co-implicated.